Hemocompatibility of folic-acid-conjugated amphiphilic PEG-PLGA copolymer nanoparticles for co-delivery of cisplatin and paclitaxel: treatment effects for non-small-cell lung cancer.

In this study, we used folic-acid-modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (FA-PEG-PLGA) to encapsulate cisplatin and paclitaxel (separately or together), and evaluated their antitumor effects against lung cancer; this study was conducted in order to investigate the antitumor effects of the co-delivery of cisplatin and paclitaxel by a targeted drug delivery system. Blood compatibility assays and complement activation tests revealed that FA-PEG-PLGA nanoparticles did not induce blood hemolysis, blood clotting, or complement activation. The results also indicated that FA-PEG-PLGA nanoparticles had no biotoxic effects, the drug delivery system allowed controlled release of the cargo molecules, and the co-delivery of cisplatin and paclitaxel efficiently induces cancer cell apoptosis and cell cycle retardation. In addition, co-delivery of cisplatin and paclitaxel showed the ability to suppress xenograft lung cancer growth and prolong the survival time of xenografted mice. These results implied that FA-PEG-PLGA nanoparticles can function as effective carriers of cisplatin and paclitaxel, and that co-delivery of cisplatin and paclitaxel by FA-PEG-PLGA nanoparticles results in more effective antitumor effects than the combination of free-drugs or single-drug-loaded nanoparticles.

Degradation behavior and biosafety studies of the mPEG-PLGA-PLL copolymer.

In a previous study, a novel biodegradable multiblock copolymer, monomethoxy(poly-ethylene glycol)-poly(d,l-lactide-co-glycolide)-poly(l-lysine) (PEAL), was developed as a new drug carrier material. It is imperative to study the biocompatibility and degradation behavior of PEAL to pave the way for clinical applications. Here, we systematically demonstrated that the PEAL copolymer has the appropriate hydrophilicity and biosafety. The degradation rate of the PEAL films was obtained by observing changes in mass, molecular weight (Mw), Mw distribution and degradation products. The degradation rate was observed to have a highly positive correlation with the pH of the medium and negative correlation with the ratio of lactic acid to glycolic acid (LA/GA). Cytotoxicity tests indicated that the degradation products of the copolymer were non-toxic to cells. In zebrafish embryos, the PEAL nanoparticles had no obvious impact on heart rate, production of reactive oxygen species, mortality, or cell apoptosis, and they were observed to have a long circulation time. Therefore, the PEAL copolymer has great potential for use as a drug carrier material.

Effect of Body Size Change on Off-Center Cervical Point and Face Doses in Patients Undergoing Nasopharyngeal Carcinoma Radiotherapy.

Nasopharyngeal carcinoma (NPC) is a clinically multiple malignant tumor. At present, with the increase in the infection rate of Epstein-Barr virus, the incidence of nasopharyngeal carcinoma is also increasing day by day. To explore the effect of body size change on off-center cervical point and face doses in patients with nasopharyngeal carcinoma (NPC) undergoing radiotherapy, in total, 100 patients with NPC from January 2019 to May 2020 in our hospital were selected for retrospective analysis, and they all received intensity-modulated radiation therapy. Bodyweight, horizontal longitudinal diameter of the odontoid process, longitudinal diameter of the third cervical spine, maximum radiation dose, and average radiation dose of normal organs in the first and last treatments were assessed, and the correlation between normal organ irradiation dose and body size was analyzed. Bodyweight, horizontal longitudinal diameter of the odontoid process, and longitudinal diameter of the third cervical spine in the last treatment were lower than those in the first treatment, with a statistically significant difference. There was no statistically significant difference in the maximum normal organ irradiation dose to the left eyeball, right eyeball, left crystalline lens, right crystalline lens, and maximum irradiation dose to optic nerve between the last treatment and the first treatment. In the last treatment, the maximum dose to the left parotid gland, right parotid gland, spinal cord, and brain stem was higher than that in the first treatment. The average irradiation dose to the left eye bulb, right eye bulb, left lens, right lens, optic nerve in the last treatment, and that in the first treatment showed no significant difference. The average dose to the left parotid gland, right parotid gland, spinal cord, and brain stem in the last treatment was higher than that in the first treatment. The irradiation dose to the left parotid gland, right parotid gland, spinal cord, and brain stem was significantly negatively correlated with body weight, horizontal longitudinal diameter of the odontoid process, and longitudinal diameter of the third cervical spine. After NPC radiotherapy, the body size of patients can change, which can have different effects on irradiation doses. Therefore, the target area and dose should be corrected during treatment to ensure the efficacy and safety of the treatment.

Radiotherapy for recurrent central Giant cell granuloma: a case report.

BACKGROUND: Central giant cell granuloma (CGCG) is a rare, non-neoplastic, benign lesion that exhibits expansive and osteolytic biological behavior. CGCG treatment and management is challenging for clinicians. CASE PRESENTATION: This report presents the treatment and management of recurrent, aggressive CGCG after surgical resection. After informed consent was obtained, the patient underwent radiotherapy. The lesion size was reduced significantly, with no evidence of recurrence or malignant transformation. CONCLUSIONS: This treatment experience indicates that radiotherapy can be used as a rescue treatment for complicated CGCG involving vital neurovascular structures of the cranial base.

Codelivery of GRP78 siRNA and docetaxel via RGD-PEG-DSPE/DOPA/CaP nanoparticles for the treatment of castration-resistant prostate cancer.

Background: Castration-resistant prostate cancer (CRPC) accounts for the majority of prostate cancer deaths, and patients with CRPC are prone to developing drug resistance. Therefore, there is a need to develop effective therapeutics to treat CRPC, especially drug-resistant CRPC. Although various nanoparticles have been developed for drug or gene delivery and control release, approaches to reproducibly formulate the optimal treatment with nanoparticles that could effectively target CRPC and bone metastasis remain suboptimal. Recently, codelivery of a chemotherapeutic agent and a small interfering RNA (siRNA) has become a promising strategy for the treatment of drug-resistant prostate cancer. Methods: In a previous study, we prepared a novel RGD-PEG-DSPE/CaP nanoparticle as an effective and biocompatible drug and gene delivery system. In this study, we further modify the nanoparticle to obtain the LCP-RGD nanoparticle, which contains a calcium phosphate (CaP) core, dioleoyl phosphatidic acid (DOPA) and RGD modified poly(ethylene glycol)-conjugated distearoyl phosphatidylethanolamine (RGD-PEG-DSPE). This drug delivery system was used for codelivery of GRP78 siRNA and docetaxel (DTXL) for the treatment of the PC-3 CRPC. Results: The nanoparticles contain the CaP core, which can effectively compress the negatively charged siRNA, while the DOPA and RGD-PEG-DSPE component can effectively carry DTXL. The arginine-glycine-aspartic acid (RGD) segment can target the prostate cancer site, as the cancer site is neovascularized. This novel nanoparticle has good stability, excellent biocompatibility, high drug and siRNA loading capacity, and an in vitro sustainable release profile. Conclusion: Codelivery of DTXL and GRP78 siRNA has enhanced in vitro and in vivo anti-prostate cancer effects which are much greater than using free DTXL and free GRP78 siRNA together. Our study also indicated that codelivery of DTXL and GRP78 siRNA have an in vitro and in vivo combinational anti-prostate cancer effect and also could effectively sensitize the cell-killing effect of DTXL; this method may be especially suitable for drug-resistant CRPC treatment.

Distribution of metastasis in the brain in relation to the hippocampus: a retrospective single-center analysis of 565 metastases in 116 patients.

OBJECTIVE: To examine the distribution of brain metastases (BM) in relation to the hippocampus, so as to determine the risk of metastasis in the hippocampus, and thus provide experimental evidence for the hippocampal avoidance (HA) in patients with BM during radiotherapy. METHODS: (1) For the retrospective analysis of 116 patients diagnosed with malignancies, confirmed as BM, from December 2014 to December 2016 at the First Affiliated Hospital of Bengbu Medical College. We obtained the T1-weighted, postcontrast axial, sagittal, and coronal Magnetic Resonance imaging (MRI) images f the patients, in supine position, using the head restraints and head thermoplastic masks to adjust the positioning, with computed tomography (CT) positioning scan ranging from the head to the mandible (layer thickness: 3 mm). CT and MRI images were fused on a Philips Pinnacle v9.8 treatment planning system;(2) Every metastasis of the 565 metastases was contoured;(3) hippocampus were contoured, and hippocampus with 5 mm expansion envelopes were analyzed;(4) Using the SPSS 16.0 software, we analyzed the relation between the distribution and age, sex, Karnofsky performance status (KPS), primary site, aggregate volume of intracranial metastases and the whole brain. The data were analyzed using a binary logistic regression analysis method, with two-sided P < 0.05 for statistical significance. RESULTS: In this study, we recruited 116 patients with 565 metastases. Among them, 1.7% (n = 2) had metastases in the hippocampus, and 11.2% (n = 13) had metastases within 5 mm of the hippocampus, of which more than half were patients with non-small cell lung cancer (n = 7). Using a binary logistic regression to analyze the relation between the metastases located within 5 mm of the hippocampus and age (P = 0.395), sex (P = 0.139), KPS (P = 0.724), primary site (P = 0.894), aggregate volume of intracranial metastases (p = 0.093) and the whole brain (p = 0.998), and none of them showed statistically significant difference between them and the metastases location (P>0.05). CONCLUSION: This study showed a low risk for the perihippocampal metastases (PHM) and no significant correlation between PHM and age, sex, KPS, primary site, aggregate volume of intracranial metastases and the whole brain. Accordingly, it is may be acceptable to avoid the perihippocampal region during whole brain radiotherapy.

Preparation and Biocompatibility Evaluation of PEG-PLL/RGD-PEG-DSPE/Phospholipid/CaP Nanoparticles.

(Arginine-Glycine-Aspartic)-methoxy polyethylene glycol-(1,2-distearoyl-sn-glycero-3-phosphoethanolaMine-N) (abbreviation: RGD-PEG2000-DSPE or RGD-PD) was successfully synthesized and verified by 1H-NMR and MALDI-TOF MS. Polyethylene glycol-poly-L-lysine/RGD-PD/phospholipid/calcium phosphate nanoparticles (PEG-PLL/RGD-PD/PL/CaP NPs or MNPs) were prepared using a novel, simple method conducted at room temperature. Transmission electron microscopy (TEM) analysis showed that the MNPs were spheres of uniform size, with a diameter of ∼30 nm, and smooth surface. Thermogravimetric analysis (TGA) revealed that the PEG-PLL/RGD-PD/PL micelle was packed in the CaP shell. MNPs had little effect on hemolysis, coagulation, cardiac oxidative stress, inflammatory response and DNA damage, indicating negligible cytotoxicity in vitro and in vivo. Experiments in Zebrafish indicated that the MNPs neither affected the survival rate and heartbeat rate, nor induced malformation and apoptosis during embryogenesis. In conclusion, these results demonstrate that the newly-developed MNPs have good biocompatibility and a great potential as drug and gene carrier.

Immune activity and biodistribution of polypeptide K237 and folic acid conjugated amphiphilic PEG-PLGA copolymer nanoparticles radiolabeled with 99mTc.

In a previous study, amphiphilic copolymer, polypeptide K237 (HTMYYHHYQHHL) and folic acid (FA) modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (K237/FA-PEG-PLGA) nanoparticles were developed and studied as a drug carrier. To further promote the clinical application of K237/FA-PEG-PLGA nanoparticles and provide guidance for future research, we need to examine their specific biodistribution in vivo. In this study, K237/FA-PEG-PLGA nanoparticles were effectively labeled by a direct method with Technetium-99m (99mTc) using stannous chloride as a reducing agent. The optimal stability of the labeled nanoparticles was determined by evaluating their radiochemical purity in serum, physiological saline, diethylenetriaminepentaacetic acid (DTPA) and cysteine solutions. The affinity of ligands and receptors was elicited by cell binding and blocking experiments in KDR/folate receptor high expressing SKOV-3 ovarian cancer cells. The nanoparticles biodistribution was studied after intravenous administration in healthy mice xenografted with SKOV-3 cells. A higher percent injected dose per gram of tissue (% ID/g) was observed in liver, kidney, spleen, blood and tumor at 3 and 9 h post-injection. Scintigraphic images revealed that the radioactivity was mainly concentrated in tumor, liver, kidney and bladder; and in the heart, lung, and muscle was significantly lower at 3 h. The radioactivity distribution in the images is consistent with the in vivo biodistribution data. Our works demonstrated that K237/FA-PEG-PLGA nanoparticles have great potential as biodegradable drug carriers, especially for tumors expressing the folate and KDr receptor.

Co-delivery of cisplatin and paclitaxel by folic acid conjugated amphiphilic PEG-PLGA copolymer nanoparticles for the treatment of non-small lung cancer.

An amphiphilic copolymer, folic acid (FA) modified poly(ethylene glycol)-poly(lactic-co-glycolic acid) (FA-PEG-PLGA) was prepared and explored as a nanometer carrier for the co-delivery of cisplatin (cis-diaminodichloroplatinum, CDDP) and paclitaxel (PTX). CDDP and PTX were encapsulated inside the hydrophobic inner core and chelated to the middle shell, respectively. PEG provided the outer corona for prolonged circulation. An in vitro release profile of the CDDP + PTX-encapsulated nanoparticles revealed that the PTX chelation cross-link prevented an initial burst release of CDDP. After an incubation period of 24 hours, the CDDP+PTX-encapsulated nanoparticles exhibited a highly synergistic effect for the inhibition of A549 (FA receptor negative) and M109 (FA receptor positive) lung cancer cell line proliferation. Pharmacokinetic experiment and distribution research shows that nanoparticles have longer circulation time in the blood and can prolong the treatment times of chemotherapeutic drugs. For the in vivo treatment of A549 cells xeno-graft lung tumor, the CDDP+PTX-encapsulated nanoparticles displayed an obvious tumor inhibiting effect with an 89.96% tumor suppression rate (TSR). This TSR was significantly higher than that of free chemotherapy drug combination or nanoparticles with a single drug. For M109 cells xeno-graft tumor, the TSR was 95.03%. In vitro and in vivo experiments have all shown that the CDDP+PTX-encapsulated nanoparticles have better targeting and antitumor effects in M109 cells than CDDP+PTX-loaded PEG-PLGA nanoparticles (p < 0.05). In addition, more importantly, the enhanced anti-tumor efficacy of the CDDP+PTX-encapsulated nanoparticles came with reduced side-effects. No obvious body weight loss or functional changes occurred within blood components, liver, or kidneys during the treatment of A549 and M109 tumor-bearing mice with the CDDP+PTX-encapsulated nanoparticles. Thus, the FA modified amphiphilic copolymer-based combination of CDDP and PTX may provide useful guidance for effective and safe cancer chemotherapy, especially in tumors with high FA receptor expression.

The biocompatibility evaluation of mPEG-PLGA-PLL copolymer and different LA/GA ratio effects for biocompatibility.

Biomaterial poly(lactic-co-glycolic acid) (PLGA), a FDA-approved material for clinical application, showed broad prospects in the past, but gradually can no longer meet present clinical developments and requirements, which we synthesized monomethoxy(polyethylene glycol)-poly(D,L-lactic-co-glycolic acid)-poly(L-lysine) (mPEG-PLGA-PLL) (PEAL) and have had some relevant reports. But studies on biocompatibility and the impacts of LA and GA ratio (LA/GA=60/40, 70/30, and 80/20) in main material have not yet been reported. Hemolysis experiment indicates that the hemolysis rate of PEAL extraction medium is less than 5%. Whole blood clotting time (CT), plasma recalcification time, activated partial thromboplastin time, prothrombin time evaluations, and dynamic CT assay show that the anticoagulant time of PEAL copolymer for blood is longer than that under negative and positive control. Protein adsorption assay indicates that PEAL films adsorb less protein than PLGA films (p<0.01); but comparing with expanded polytetrafluoroethylene, the aforementioned difference is not significant (p>0.05). Complement activation test shows that PEAL surface does not induce complement activation. CCK8 measurement shows that the relative growth rates of Huh7, L02, and L929 cells co-incubated with PEAL nanoparticles (NPs) are more than 90%. PEAL NPs co-incubated with 5% foetal bovine serum or 2% bovine serum albumin, through dynamic light scattering assay, remain stable. Different concentrations of PEAL NPs co-incubated with zebrafish embryos at 6-72 h post fertilization show that comparing with negative control, 10, 100, or 500 µM of NPs for embryos development has no significant effects (p>0.05), only 1000 or 2000 µM of NPs has some effects (p<0.05). It is concluded that the PEAL copolymer, with excellent biocompatibility, proves to be a high-safety dose as drug carrier and implant candidate in vivo.